Our poor understanding of the molecular mechanisms that underlie the cognitive and behavioral impairments that characterize Alzheimer?s disease stands as a critical barrier to identifying effective treatments for Alzheimer?s disease. This project seeks to address this gap in our understanding by examining the ability of SUMOylation, a post-translational modification during which small peptides called small ubiquitin-like modifiers (SUMOs) covalently attach to lysine residues on target substrates, to control the pathological actions of tau ? a central component in the molecular etiology of the disease. SUMOylation is a reversible process with various effects on protein function, including regulation of localization, stability and activity of many cellular proteins, as well as nuclear integrity, chromosomal segregation and gene expression. There are three known SUMO paralogs in vertebrate brains: SUMO1-3, with SUMO2 and 3 sharing ~95% sequence homology (and not functionally differentiated) often collectively referred to as SUMO2/3. Interestingly, SUMOylation is dysregulated in the hippocampus of Alzheimer?s Disease patients. In preliminary studies we have been able to link tau SUMOylation to tau aggregation and toxicity with SUMO2 conjugation (but not SUMO1) protecting against tau aggregation and toxicity. SUMO2 was also found to decrease aggregated tau release. Moreover, mimicking SUMO2 covalent binding to tau rescued the oligomeric tau-induced impairment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation, and memory loss in a mouse model of fronto-temporal dementia. In this proposal, we will build on these observations by pursuing the following specific aims: 1) determine if upregulating SUMO2 conjugation rescues tau-induced defects in synaptic function; 2) determine if upregulating SUMO2 conjugation rescues tau-induced memory defect in mice; 3) test whether the rescuing effects of upregulating SUMO2 conjugation depend upon modulation of tau oligomer formation. These aims will be addressed through a combination of electrophysiological, behavioral, biophysical, and biochemical techniques in wild-type and genetically modified mice. Upon the completion of these experiments, we will identify the mechanisms whereby SUMOylation controls the development of tau-related impairments in Alzheimer?s disease and in fronto-temporal dementia, and test the possibility that interventions that target SUMO2 conjugation could constitute an effective therapeutic approach for their treatment.